ethyl 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5 ml), to furnish the required compound. 1H-NMR (DMSO-d6) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d, 1H). MS m/z: 500.1 (M++1). The solid that separated out from the reaction mixture was filtered washed with isopropylalcohol (5 ml)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5 ml), to furnish the required compound. 1H-NMR (DMSO-d6) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d, 1H). MS m/z: 500.1 (M++1). The solid that separated out from the reaction mixture was filtered washed with isopropylalcohol (5 ml)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a fritted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. HPLC (4 minute 10-90 gradient) tR 1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1 H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1 H), 7.51 (d, J=7.9, 1 H), 6.24 (bs, 2 H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1 H), 2.35 (s, 3 H), 2.14 (s, 3 H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2 H), 0.58 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc and ether was added to the residue a solid precipitated The solid was collected on a fritted funnel was washed with EtOAc and ether

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a fritted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. HPLC (4 minute 10-90 gradient) tR 1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1 H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1 H), 7.51 (d, J=7.9, 1 H), 6.24 (bs, 2 H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1 H), 2.35 (s, 3 H), 2.14 (s, 3 H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2 H), 0.58 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc and ether was added to the residue a solid precipitated The solid was collected on a fritted funnel was washed with EtOAc and ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-cyano-3,3-bis(methylthio)acrylate (3.8 g, 17.49 mmol) was dissolved in 70 mL ethanol and (4-methoxyphenyl)methanamine (2.88 g, 20.99 mmol) was added. The reaction was stirred at reflux for 2 h. The solvent was evaporated to give 6.5 g (100% yield) of the title compound that was used in the next step without any further purification. Purity 80%. at reflux for 2 h The solvent was evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester (5.00 g, 23.0 mmol) in dry ethanol (100 mL) is added phenylhydrazine (2.28 mL, 23.0 mmol). The reaction mixture is heated to reflux for 2 h before removal of the solvent. The resulting solid is recrystallized from EtOH (20 mL) to provide 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid product; HPLC-MS calculated for C13H15N3O2S (M+H+) 278.1, found 278.1. The reaction mixture is heated to reflux for 2 h before removal of the solvent The resulting solid is recrystallized from EtOH (20 mL)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a flitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. HPLC (4 minute 10-90 gradient) tR 1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1 H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1 H), 7.51 (d, J=7.9, 1 H), 6.24 (bs, 2 H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1 H), 2.35 (s, 3 H), 2.14 (s, 3 H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2 H), 0.58 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc and ether was added to the residue a solid precipitated The solid was collected on a flitted funnel was washed with EtOAc and ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5 ml), to furnish the required compound. 1H-NMR (DMSO-d6) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d, 1H). MS m/z: 500.1 (M++1). The solid that separated out from the reaction mixture was filtered washed with isopropylalcohol (5 ml)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a fritted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. HPLC (4 minute 10-90 gradient) tR 1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1 H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1 H), 7.51 (d, J=7.9, 1 H), 6.24 (bs, 2 H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1 H), 2.35 (s, 3 H), 2.14 (s, 3 H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2 H), 0.58 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc and ether was added to the residue a solid precipitated The solid was collected on a fritted funnel was washed with EtOAc and ether